Summary: This project aims at identifying optimal treatment strategies to slow or prevent degeneration and the increase the function of brain cells affected in Alzheimer's disease. To this aim, presently available and novel neurotrophins and neurotrophin mutants and chimeras will be evaluated for their effects on basal forebrain cholinergic and GABAergic neurons, on neurons in the hippocampus and on cortical cells. Factors selected using cell culture systems will be tested in the rat lesion model of the partial fimbrial transection resulting in loss of cholinergic and GABAergic cells in the basal forebrain and in partial deafferentation of the hippocampus. Trophic factors will be administered intracerebrally and their actions will be assessed using molecular and cellular markers of neuronal function. Finally, it is attempted to develop a treatment approach involving neurotrophin mechanisms based on NT-3 enhancement by small molecular weight compounds. In specific aim #1, actions of trophic molecules pre-screened on PC12 cells and peripheral neurons (Project 1) will be characterized in cell culture systems of brain neurons which earlier have been shown to be useful predictors for trophic actions occurring in vivo. In specific aim #2, neuroprotective effects of neurotrophins and neurotrophin mutants in adult rats will be quantified and the respective roles of TrkA and p75NGFR in these effects will be examined. In specific aim #3, effects of septohippocampal lesion and of chronic neurotrophin treatment on the responsiveness of neurotrophin receptors in rat basal forebrain and hippocampus will be measured. In close collaboration with Project 3 (D. Price and V. Koliatos), it will further be attempted to assess the functional status of NGF receptors in human normal aged and AD postmortem brains. In addition to these studies which are aimed at identifying an optimal treatment using intracerebral application of neurotrophin protein, in aim #4, a novel approach will be tested to stimulate, or enhance NT-3 induced, neurotrophin mechanisms in rat hippocampus and basal forebrain. The studies of Project #2 will identify optimal approaches to neurotrophin protection of brain cells degenerating in AD.